title: TRIP-1 regulates TGF-β1-induced epithelial-mesenchymal transition of human lung epithelial cell line A549.
abstract: Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells undergo conversion to a mesenchymal phenotype contributing to wound repair by fibrosis and to cancer cell acquisition of invasive ability. Recently, we showed that type II TGF-β receptor interacting protein-1 (TRIP-1), a protein identified as a phosphorylation target of the TGF-β type II receptor kinase and as a functional component of eukaryotic translation initiator factor 3 (eiF3) multiprotein complex, is a novel modulator of fibroblast collagen contraction, an important step in wound repair stimulated by TGF-β1 action. TGF-β1 drives EMT, but it is not known whether TRIP-1 expression influences EMT induction. To investigate whether TRIP-1 plays a role in EMT induction we studied the effect of downregulating TRIP-1 expression in the well-characterized A549 model of TGF-β1 induction of EMT. Here we report that short hairpin RNA (shRNA)-mediated depletion of TRIP-1 gene transcripts in A549 cells promotes EMT as assessed by changes in phenotypic markers, morphology, and migrative ability. Knockdown of TRIP-1 dramatically increased A549 responsiveness to TGF-β1 induction of EMT. Mechanistically, a pathway involving increased TGF-β type II receptor level, enhanced Smad3 phosphorylation, and the transcription factor SLUG is implicated. Altogether, the findings point to regulation of endogenous TRIP-1 protein expression as a potential strategy to target EMT, and related invasive behavior, in cancer cells.
authors.affiliation: Department of Pediatrics/Neonatology Section, Children's Mercy Hospitals and Clinics/University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Perez
authors.forename: Angels
authors.initials: A
authors.lastname: Navarro
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Rezaiekhaligh
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Mabry
authors.forename: Ikechukwu I
authors.initials: II
authors.lastname: Ekekezie
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung; D034741:RNA, Small Interfering / Q000494:pharmacology; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D039621:Eukaryotic Initiation Factor-3; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C096013:EIF3I protein, human